细胞色素 P450 催化的烷基胺化合物分子内环化中 C?H 活化的区域选择性,International Journal of Quantum Chemistry

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细胞色素 P450 催化的烷基胺化合物分子内环化中 C?H 活化的区域选择性
International Journal of Quantum Chemistry ( IF 2.3 ) Pub Date : 2023-07-04 , DOI: 10.1002/qua.27193
Dan Qin ₁ , Lu Dong ₁ , Xue Jiang ₁ , Lijun Yang _{1,

2}

Affiliation

采用密度泛函理论研究了细胞色素P450介导的2-氨基酰胺化合物分子内环化为咪唑啉酮的反应机理。环化反应涉及三个步骤：夺氢、中间体脱水为两性离子和最终闭环。有趣的是，高自旋（HS）态 P450 催化的脱水表现出与低自旋态等传统过程不同的机制。在HS途径中，夺氢后的羟基不会反弹，而是产生中间体，这使得第二次夺氢具有区域选择性。区域选择性导致两性离子的不同中间体和机制，这意味着高自旋态和低自旋态 P450 的不同功能。烷基胺氮和酰胺基团是实现 HS 途径区域选择性的关键基团。分子结构的微小变化就能影响分子的转变过程，表明电子态对反应过程的复杂调控。研究结果为P450酶和底物结构共同决定区域选择性奠定了理论基础。该研究为含氮杂环药物的药物设计、药物代谢和合成奠定了基础。

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Regioselectivity of C?H activation in cytochrome P450-catalyzed intramolecular cyclization of alkylamine compounds

The reaction mechanism of cytochrome P450-mediated intramolecular cyclization of 2-aminoamide compounds to imidazolinone was studied by density functional theory. The cyclization reaction involves three steps: hydrogen abstraction, dehydration of intermediates to zwitterions and final ring closure. Interestingly, high spin (HS) state P450-catalyzed dehydration exhibits a mechanism distinct from conventional processes such as in low spin state. In HS pathways, the hydroxyl group after hydrogen abstraction does not rebound but produce an intermediate, which makes the second hydrogen abstraction regioselective. Regioselectivity leads to diverse intermediates and mechanisms to zwitterion, which implies different functions of the high and low spin states P450. The alkylamine nitrogen and amide group are key groups to enables regioselectivity of in HS pathway. Small changes of molecular structure can affect the molecular transformation process, indicating the complex regulation of electronic state to reaction process. The results lay the theoretical basis for the regioselectivity determined by P450 enzyme and substrate structure together. The research establishes a foundation for the drug design, drug metabolite, and synthesis of nitrogen-containing heterocyclic drugs.

更新日期：2023-07-04

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